Aminoglycosides Flashcards
Aminoglycoside options
-Amikacin
-Gentamicin
-neomycin
-apramycin
Gentamicin formulations
- Gentocin- sterile injectable solution (IM, SC, IU but given IV off label)
- Otomax, Mometamaxx
-topical ointments for otitis externa
-includes an antifungal - Topagen
-topical spray for dermal lesions
Amikacin formulations
1.Amiglyde-V
-sterile injectable solution
-labelled only for IU use in mares but often given off label IV in small animals and equine
**Generally more potent than Gentomicin.. but narrower spectrum of activity
Neomycin
-various calf scour boluses, water soluble powders for food animals
-skin/ear ointments
-antimicrobial preservative in many vaccines
Apramycin
-Apralan oral solution for swine scours caused by E. coli
Aminoglycasides mechanism of action
Bind to bacterial ribosomal 30S subunit
-causes incorrect tRNA translation
-disrupts bacterial protein synthesis
-results in increased bacterial membrane permeability
Factors allowing for aminogylcosides to access the bacteria
- Need oxygen so very poor efficacy in anaerobic environment
- Local pH
-basic pH= aminoglycosides non ionized, easier to transport in but can diffuse out
-acidic pH= Aminoglycosides more ionized, less transport in but then ion trapped - Purulent material in abscesses can inactivate aminoglycosides
Aminoglycosides spectrum of activity
- gram -
-especially enteric bacteria (including pseudomonas) - Activity against staph spp
-includes some MRSA/MRSP - Some activity against enterococcus, mycobacteria, mycoplasma
What are aminoglycosides not effective against?
- less activity against strep spp
*especially amikacin - intracellular pathogens
-including salmonella - Anaerobes
Ways bacteria can become Resistance to aminoglycosides
- Plasmid-mediated enzymes degrade aminoglycosides and prevent binding to ribosome 30S subunit
**most important for determining clinical susceptibility
NOTE: Amikacin is the last to give out/least effected - decreased permeability = adaptive resistance
- Chromosomal resistance
-changes to 30S binding sites so mutations don’t usually produce clinical resistance
First exposure adaptive resistance
Bacteria takes up aminoglycosides initially and then there is a decrease in AG uptake for 1-2hours
*lasts up to 16hrs post exposure then partial return of susceptibility
-Resistance accumulates with increasing # of doses
Dosing to avoid first exposure adaptive resistance
Infrequent dosing of high doses
*this decreases the adaptive resistance effect
Amikacin vs. Gentamicin
Amikacin is more potent and broader (more gram negs but decreased Strep activity)
-less effected by bacterial resistance
Oral administration of aminoglycosides
Very poor!
-yet often found in calf scour boluses (very leaky gut due to damage= drug residues)
-some absorbed during enteritis or with high doses
Parenteral administration of aminoglycosides
Good absorption IM/SC
-but toxicity concerns so often given IV extralabel
Some systemic absorption IU (label) or IMM (ELDU) doses
Local delivery: hopefully minimal absorption
Aminoglycosides elimination
RENAL
-glomerular filtration
-during renal disease, see decreased GFR and clearance of AG (**DOSE MODIFICATION NEEDED)
-binds to proximal tubule cells
PK-PD aminoglycosides
CONCENTRATION-DEPENDENT ANTIMICROBIAL
Cmax: MIC>10
-increased trough (low drug conc.) plasma concentration correlates with adverse effects
-long post antibiotic effect
-clinical implication: high dose, but only SID or less is most rational.
Vd and elimination rates
-Low Vd
-Rapid elimination 1-2hrs… fast from plasma but not in tissues
Adverse events of aminoglycosides
- Nephrotoxicity
- Ototoxicity
- Neuromuscular blockade
- Drug interactions
- Drug residues
Nephrotoxicity
Acute tubular necrosis
**most common
Steps:
AG accumulates in renal proximal tubule cells
1. In tubular lumen, cationic AG binds to negative charged phosphotidylinositol on tubular cells
2. AG enters cell via carrier mediated pinocytosis
3. AG sequestered in lysosomes and eventually they rupture which kills proximal tubule cells
Protective conditions of nephrons with aminoglycosides
- Increase GFR
-by fluid therapy (HYDRATION)
-by high protein in diet - SID, high dosing (vs. multiple smaller doses)
-rapid elimination in filtrate so decrease overall contact - High calcium or protein in diet
-cations compete with positive charges on aminoglycosides for tubule cell binding
Ototoxicity
-occurs in the ear affects hearing and/or balance
-same mechanism of nephrotoxicity
-not as noticeable by owners… more of a longer term thing
Diuretics impact on nephrotoxicity and ototoxicity
Seem to be exacerbated by diuretics (flush out of kidney BUT animal loses urine and is dehydrated which is where the risk comes in)
**Diuretics not recommended BUT fluids are recommended
Neuromuscular blockage with aminoglycosides
Rare
-related to block of ACh at motor end plate
-treat with calcium
Drug interactions with aminoglycosides
- pH incompatibilities when mixed in same syringe
*Solution: one drug, one syringe - Synergy with beta-lactams (in vitro only)
-putting drug categories together does not give you a better outcome BUT it does give you a broader range of spectrum - Avoid using with other nephrotoxic drugs
Aminoglycosides in food animals
Drug residues occur
-most drug gone from plasma in 1 day
-very slow depletion from the kidney (high even a year later)
*neomycin and gentamicin residue violations are common
Detecting peak and trough measurements
Peak= taken 0.5-1hr after dose
Trough= sample 8hrs after dose if dosing every 24 hrs
Send to lab. Rare. not really done anymore
Monitoring of Nephrotoxicity
- increased urine gamma glutamyl transferase enzyme and urine [GGT:Creatinine] ratio
-creatinine is filtered but not excreted or absorbed
-2-3x baseline of creatinine within 3 days of a nephrotoxic dose (nephrons die) - Proteinuria
-not a sensitive test; takes a long time; lots of things can cause protein increase in urine - Increased serum urea nitrogen and serum creatinine
-too long, not seen for 7days and damage is already done
How to prevent toxicity from aminoglycosides?
-fluids
-SID, high dose
Local drug therapy of aminoglycosides
- REgional perfusion
-torniquet on, infuse high dose within distal limb
-intra-osseous or intra-articular - Antimicrobial impregnated beads (PMMA)
-powder with dose of antimicrobial in beads, sterilized and placed at injection site.
*might not be great because slow and increased exposure at that side
